Panic disorder is a common and genetically complex mental illness, characterized by recurrent and unexpected panic attacks. It exhibits a lifetime prevalence rate of between 1.2/100 to 2.4/100 in the general population (Weissman, M. M. et al., Arch. Gen. Psychiatry, 1997; 54, 305-309). Family studies have consistently shown a higher prevalence ranging from between 7.7% to 20.5% in the first-degree relatives of probands. Twin studies have shown concordance rates of 25% for MZ twins and 10% for DZ twins (Skre, I. et al., Acta Psychiatr. Scand. 1993; 88, 85-92). These epidemiological studies suggest involvement of genetic factors in the development of this disease.
Cholecystokinin (CCK) is a neuropeptide as well as a gastrointestinal peptide hormone, and is reported to have the relation with pathogenesis of panic disorder and schizophrenia. The carboxy terminal tetrapeptide of CCK (CCK-4), expressed in the brain, is thought to act as a neurotransmitter and/or neuromodulator. It provokes panic attacks in subjects with panic disorder and normal controls (Bradwejn et al., 1990; Can. J. Psychiatry 35, 83-85; and de Montigny et al., 1989; Arch Gen Psychiatry 46, 511-517). Patients with panic disorder have a higher sensitivity to CCK-4 than controls (Bradwejn et al., 1991; Arch. Gen. Psychiatry 48, 603-610). Furthermore, this panicogenic effect of CCK-4 is inhibited by antagonists of CCK B receptor (Bradwejn et al., 1994; Arch. Gen. Psychiatry 51, 486-493) which constitutes a large proportion of the CCK receptors in the human brain (de Weerth et al., 1993; Biochem. Biophys. Res. Commun. 194, 811-818). These findings have intensified research into elucidating the role of CCK in panic disorder.
CCK-like peptides, mainly the carboxy terminal octapeptide of CCK (CCK-8), co-localize with dopamine in mesolimbic dopaminergic neurons (Hokfelt et al., 1980; Nature 285, 476-478). In rats, CCK B receptor antagonists are shown to decrease the number of spontaneously active midbrain dopamine neurons (Rasmussen et al., 1991; Eur. J. Pharmacol. 209, 135-138). In humans, CCK-8 is reported to have an anti-psychotic effect (Moroji et al., 1982; Arch. Gen. Psychiat. 39, 485-486), inferring a possible role in the pathology of schizophrenia.
Two groups simultaneously reported a single nucleotide polymorphism (SNP), −36C>T in the 5′-upstream region of the CCK gene. Wang et al., (1998) Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81, 228-234, showed that the −36T allele was weakly associated with subjects manifesting panic attacks (P<0.05) but not with panic disorder. In a case-control study of schizophrenia, Bowen et al., (1998) Mol. Psychiatry 3, 67-71, found no association between this SNP and the disease.
In general, the polymorphism, such as SNPs, which exists frequently in the human genome, is thought to have a relationship with a specific disease or constitution. Therefore, it is desirable to find the polymorphism which is used for the diagnosis and treatment of these diseases and to provide high quality order-made medical care. However, in the prior art, no functional polymorphisms associated with psychiatric disease have been reported in the CCK gene.